Following this review, members of
the trauma-list are signing
a letter to present to the American College of Surgeons
ATLS subcommittee asking them to revise the ATLS position
on the use of steroids in spinal cord injury. If you agree
with the evidence review below, please take a moment to
read and add your name to the letter in the TraumaWiki:
Steroids
for SCI open letter.

Comments Animal studies
subsequently determined that dose of methylprednisolone
used in NASCIS 1 was below the therapeutic threshold to
observe any potential beneficial effect. Subsequent trials
used higher dosing regimens. Nevertheless, NASCIS I demonstrated
an increased incidence of adverse events even at these
dose levels.

Neurologic outcome:
Patients were examined at admission, 6 weeks, 6 months
and 1 year. Motor strength was measured using the American
Spine Injury Association (ASIA) 0-5 scale in 14 muscle
groups, giving a maximum possible score of 70. Pin prick
& touch sensation were assessed in 29 dermatomes.
Maximum sensory score was 58. Analysis only used scores
from the right side of the body. There was no mention
of left-sided scores, although both sides were examined.

There was no difference in motor score
between treatment groups at any time point. There was
a statistically significant improvement in pinprick (3.4/58)
and light touch (3.8/58) scores at 6 months which was
lost at 1 year.

Safety & Adverse events:
Wound infection and pulmonary embolus were doubled in
the steroid group (non-significant, study not sufficiently
powered).

Post-hoc analyses All
the reported positive results from the NASCIS 2 trial
are from post-hox subgroup analysis.

When patients were stratified by time
to treatment, patients receiving steroids within 8 hours
had a statistically significant improvement of 5 points
on the motor score at 6 months and 1 year (p=0.03). Patients
treated with steroids more than 8 hours after injury had
a worse neurological outcome, but this did not achieve
significance.

Comments:

Statistical significance:

NASCIS 2 was a negative study. The Level
1 evidence from this data is that there is no difference
between methylprednisolone and placebo in the outcome
of spinal cord injury. Data from post-hoc analyses cannot
be classed as Level 1 or 2 evidence (or even level 3).

The 8-hour cut-off point for the post-hoc
analysis appears completely arbitrary. This splits the
patients into 183 (38%) that randomized before 8 hours
and 304 after. Control patients in the pre-8 hour administration
category had significantly worse outcomes than those in
the post-8 hour category, a difference which could entirely
account for the statistically significant improvement
seen in the steroid group.

NASCIS 2 allows for 78 potential discrete
post-hoc subgroup analyses based on time of administration.
By chance, 1 in 20 of these would be expected to be statistically
significant at a p of 0.05. Furthermore, the NASCIS 2
statistical analysis includes over 60 t-tests for comparing
neurological outcomes. There are no corrections for multiple
comparisons, and no analysis of variance or multivariate
statistical techniques were employed. Additionally, much
of the data is thought to be non-parametric, and hence
the t-test is not appropriate. It is unlikely that any
statistical significance would be observed if correct
statistical methodology was used.

Clinical significance:

The post-hoc analysis identified a statistically
significant improvement of 5 motor points improvement
at 1 year. Is this clinically significant? An improvement
of 5 motor points in one muscle group is unlikely - but
even so would not confer any increased functionality on
a spinal cord injured patient. Similarly, and increase
of 1 motor point across 5 different muscle groups will
also have little impact on functional ability and independence.
The mean motor and sensory scores between steroid and
placebo groups in NASCIS 2 are shown below:

Neurologic outcome:
Neurological assessment was almost identical to the NASCIS
2 study.

There was no significant difference
in outcome between treatment groups.

Safety & Adverse events:
There was a trend towards an increase in septic complications
in the methylprednisolone group (66% vs. 45%) although
this did not achieve statistical significance.

Post-hoc Analyses:
Post-hoc subgroup analyses identified a statistically
significant increase in the number of patients who experienced
an improvement in sensation for those patients who received
steroids (68% vs 32%).

Comments: 41 Exclusions
after randomization (primarily for protocol violations)
make it impossible to clearly assess this study as Level
1 evidence.

Admission characteristics between the
two groups were different in terms of severity of spinal
cord injury (Frankel grade) and neurologic scores for
motor and pinprick.

If the post-hoc analyses identified
more patients in the steroid arm experienced a sensory
improvement, then more patients in the control arm must
have experienced a motor improvement, as overall neurological
outcome was unchanged between the two groups.

Neurologic outcome:
Patients were examined at admission, 6 weeks, 6 months
and 1 year. Motor strength was measured using (ASIA) 0-5
scale in 15 muscle groups, although the extra group was
subsequently excluded, giving a maximum possible score
of 70. Pin prick & touch sensation were assessed in
29 dermatomes. Maximum sensory score was 58. Disability
was scored using the Functional Independence Measure (FIM)
to try to interpret the functional significance of any
improvement in motor score. Only right sided deep pain
& pressure, left sided light touch & motor scores
used in analyses, despite both being examined.

There was no significant difference
in motor score between treatment groups at any time point.

Safety & Adverse events:
Mortality due to respiratory complications was 6 times
higher in the 48-hour group (p=0.056). There was a 2x
increase in the incidence of severe pneumonia and a 4x
increase in severe sepsis in the 48-hour group compared
to the 24-hour group. This was not statistically significant
but the study was underpowered for this analysis.

Post-hoc analyses All
the reported positive results from the NASCIS 3 trial
are from post-hox subgroup analysis.

Patients were stratified by time to
treatment into those treated less than 3 hours from injury
and 3-8 hours from injury. There was no difference in
outcome for those patients receiving steroids within 3
hours of injury. Only for patients treated between 3 and
8 hours of injury was there a 5-point improvement in motor
scores at 1 year (p=0.053). There was no difference in
sensory outcome. Disability as measured by FIM was also
unchanged at 1 year (there was a statistically significant
improvement in sphincter control of 1/14 points at 6 months
which was lost at 1 year).

Comments:

Statistical significance:

NASCIS 3 was a negative study. As with
NASCIS 2, The Level 1 evidence from this data is that
there is no difference between methylprednisolone and
placebo in the outcome of spinal cord injury. Data from
post-hoc analyses cannot be classed as Level 1 or 2 evidence
(or even level 3).

The post-hoc analysis of subgroups receiving
steroids in 0-3 hours or 3-8 hours is completely arbitrary.
Patients who received steroids early did not gain any
benefit from steroids (70% of the study population). Ensuing
statistically significant results are almost certainly
due to random events.

NASCIS 3 allows for 36 potential discrete
post-hoc subgroup analyses based on time of administration.
By chance, 1 in 20 of these would be expected to be statistically
significant at a p of 0.05. Again, as with NASCIS 2, NASCIS
3 statistical analysis includes over 100 t-tests for comparing
neurological outcomes. There are no corrections for multiple
comparisons, and no analysis of variance or multivariate
statistical techniques were employed. Additionally, much
of the data is thought to be non-parametric, and hence
the t-test is not appropriate. It is unlikely that any
statistical significance would be observed if correct
statistical methodology was used.

Clinical significance:

The post-hoc analysis identified a statistically
significant improvement of 5 motor points improvement
at 1 year. As with the NASCIS 2 results, the clinical
significance of this improvement is doubtful. Indeed,
the FIM measurements showed no difference in the level
of disability. The mean motor and sensory scores between
steroid and placebo groups in NASCIS 3 are shown below:

Petitjean, Pointillard, France 1998,
2000

Design Single centre,
prospective, randomized, double-blind trial.

Patients: 106 patients,
hospitalised within 8 hours of injury. 100 patients available
for follow-up at one year. Policy of early surgery. 76%
operated on within 24 hours, 46% within 8 hours of injury.

Neurologic outcome:
Patients were examined at admission and 1 year by a trained
neurologist blinded to the treatment..

There was no significant difference
in ASIA score between treatment groups at one year. There
was also no significant difference overall in those patients
who received steroids (54) and those who did not (52).
Two-way ANOVA showed no evidence of interaction between
methylprednisolone and nimodipine.

Safety & Adverse events:
There was a trend towards an increase in septic complications
in the methylprednisolone group (66% vs. 45%) although
this did not achieve statistical significance.

Comments: Not only
was there no significant difference in outcome in this
study, but not even a trend to improved outcome in this
study.

Neurologic Outcome:
There was no difference in disability outcome between
those patients who received steroids and those who did
not.

Safety & Adverse events:
There was a trend towards an increase in infectious complications
in the methylprednisolone group although this did not
achieve statistical significance.

Comments: There was
equivalent outcome in steroid and no-steroid groups, despite
the control group being older and more severely injured.

Poynton, Ireland 1995

Design: Retrospective
review

Patients: 71 consecutive
patients with acute spinal cord injury. 63 patients available
for follow-up, mean 30 months. Patients admitted more
than 8 hours following injury were not given steroids
and were used as controls.

Neurologic Outcome:
Patients were assessed with ASIA scores on admission,
on transfer to rehabilitation and at follow-up.

There was no difference in disability
outcome between those patients who received steroids and
those who did not.

Safety & Adverse events:
There was a trend towards an increase in infectious complications
in the methylprednisolone group although this did not
achieve statistical significance.

Comments: There was
equivalent outcome in steroid and no-steroid groups, despite
the control group being older and more severely injured.

Safety & Adverse events:
There was significant increase in the incidence of infections
in the steroid group. The dexamethasone group had a statistically
significant increase in the number of gastrointestinal
complications, and the methylprednisolone group had a
statistically significant increase in the incidence of
pancreatitis.